Progress in the Chemistry of Cytochalasans
73
3 Biological Activities of Cytochalasans
To understand the biological activity of cytochalasans, first the cytoskeleton must
be considered. The cytoskeleton is a network extending throughout a cell, which
not only supports the cell, but also provides its shape, and organizes and tethers the
organelles, and has roles in molecular transport, cell division, and cell signaling. A
cytoskeleton occurs in all cells, including eukaryotic and prokaryotic cells, although
the proteins that it is made of vary between organisms [200, 201]. Eukaryotic cells are
complex cells that have a nucleus and organelles, and cells of plants, animals, fungi,
and protists are all eukaryotic. The eukaryotic cytoskeleton consists of three types
of filaments, which are elongated chains of proteins: microfilaments, intermediate
filaments, and microtubules. Prokaryotic cells are less complex, with no true nucleus
or organelles except for ribosomes, and they are found in the single-celled organisms, namely, bacteria and archaea. It was once thought that prokaryotic cells did not
possess cytoskeletons, but advances in visualization technology and structure determination led to the discovery of filaments in these cells in the early 1990s [201]. A
series of discoveries revealed that functional analogs of actin (MreB), tubulin (FtsZ)
and intermediate filaments (crescentin) occur in prokaryotes. Moreover, it is now
generally accepted that eukaryotic microtubules and actin filaments originate from
these prokaryotic homologs [202]. Microfilaments are composed primarily of polymers of fibrous actin (F-actin) and the monomeric form of this protein, globular actin
(G-actin), and these two forms exist in equilibrium in the cell. The microfilaments
are present in bundles and form a three-dimensional (3D) intracellular meshwork.
There is extensive intracellular binding and cross-linking with other intracellular
proteins, such as myosin, lamin and spectrin [203]. Of the three types of protein
fibers in the cytoskeleton, microfilaments are the narrowest, and they have a diameter of about 6 nm. The functions of microfilaments involve cell membrane motility,
cytokinesis, endo- and exocytosis, secretion, vesicle transfer, cell shape maintenance,
cell contractility, and affording mechanical stability.
As mentioned earlier, cytochalasans are a group of structurally diverse fungal
metabolites, and their name is derived from the Greek “kytos-chalasis”, meaning cell
relaxation [204]. In a pioneering paper from 1972, actomyosin from rabbit muscle—
the active protein complex of actin and myosin, was identified as a direct binding
partner of cytochalasin B (110). Later on, studies by several groups revealed that
cytochalasins B (110) and D (2) inhibit, but not completely arrest, actin filament
elongation, and they specifically interact with the actin filament network by capping
the barbed ends, and thereby altering the dynamic properties of microfilaments. In
2008, Trybus and coworkers achieved the crystallization of cytochalasin D (2) in a
complex with actin and the exact binding relationship between cytochalasin and actin
was clarified (Plate 3) [205, 206]. Thus, cytochalasans are known as microfilamenttargeting molecules, which exhibit a wide range of biological activities, by interfering
with several cellular processes involving cytoskeleton formation.
73
3 Biological Activities of Cytochalasans
To understand the biological activity of cytochalasans, first the cytoskeleton must
be considered. The cytoskeleton is a network extending throughout a cell, which
not only supports the cell, but also provides its shape, and organizes and tethers the
organelles, and has roles in molecular transport, cell division, and cell signaling. A
cytoskeleton occurs in all cells, including eukaryotic and prokaryotic cells, although
the proteins that it is made of vary between organisms [200, 201]. Eukaryotic cells are
complex cells that have a nucleus and organelles, and cells of plants, animals, fungi,
and protists are all eukaryotic. The eukaryotic cytoskeleton consists of three types
of filaments, which are elongated chains of proteins: microfilaments, intermediate
filaments, and microtubules. Prokaryotic cells are less complex, with no true nucleus
or organelles except for ribosomes, and they are found in the single-celled organisms, namely, bacteria and archaea. It was once thought that prokaryotic cells did not
possess cytoskeletons, but advances in visualization technology and structure determination led to the discovery of filaments in these cells in the early 1990s [201]. A
series of discoveries revealed that functional analogs of actin (MreB), tubulin (FtsZ)
and intermediate filaments (crescentin) occur in prokaryotes. Moreover, it is now
generally accepted that eukaryotic microtubules and actin filaments originate from
these prokaryotic homologs [202]. Microfilaments are composed primarily of polymers of fibrous actin (F-actin) and the monomeric form of this protein, globular actin
(G-actin), and these two forms exist in equilibrium in the cell. The microfilaments
are present in bundles and form a three-dimensional (3D) intracellular meshwork.
There is extensive intracellular binding and cross-linking with other intracellular
proteins, such as myosin, lamin and spectrin [203]. Of the three types of protein
fibers in the cytoskeleton, microfilaments are the narrowest, and they have a diameter of about 6 nm. The functions of microfilaments involve cell membrane motility,
cytokinesis, endo- and exocytosis, secretion, vesicle transfer, cell shape maintenance,
cell contractility, and affording mechanical stability.
As mentioned earlier, cytochalasans are a group of structurally diverse fungal
metabolites, and their name is derived from the Greek “kytos-chalasis”, meaning cell
relaxation [204]. In a pioneering paper from 1972, actomyosin from rabbit muscle—
the active protein complex of actin and myosin, was identified as a direct binding
partner of cytochalasin B (110). Later on, studies by several groups revealed that
cytochalasins B (110) and D (2) inhibit, but not completely arrest, actin filament
elongation, and they specifically interact with the actin filament network by capping
the barbed ends, and thereby altering the dynamic properties of microfilaments. In
2008, Trybus and coworkers achieved the crystallization of cytochalasin D (2) in a
complex with actin and the exact binding relationship between cytochalasin and actin
was clarified (Plate 3) [205, 206]. Thus, cytochalasans are known as microfilamenttargeting molecules, which exhibit a wide range of biological activities, by interfering
with several cellular processes involving cytoskeleton formation.